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American Journal of Medical Genetics Part A 143A:2343 – 2346 (2007)

Research Letter

Fetal Trisomy 5 Mosaicism: Case Report and Literature Review
Nicoletta Villa,1 Serena Redaelli,1,4 Cesarina Borroni,2 Carla Colombo,2 Nadia Roncaglia,3 ` Elena Sala,1 Francesca Crosti,1 Anna Cappellini,1 and Leda Dalpra1,4*
1 Medical Genetics Lab, HSGerardo, Monza, Italy Neonatal Intensive Care Unit, HSGerardo, Monza, Italy 3 Obstetric & Gynecological Clinic, HSGerardo, Monza, Italy 4 Department of Neuroscience & Biomedical Technologies, University of Milan-Bicocca, Italy 2

Received 11 May 2007; Accepted 24 May 2007

How to cite this article: Villa N, Redaelli S, Borroni C, Colombo C, Roncaglia N, Sala E, Crosti F, Cappellini A, ` Dalpra L. 2007. Fetal trisomy 5 mosaicism: Case report and literature review. Am J Med Genet Part A 143A:2343–2346.

To the Editor:

Fetal mosaicism can be suspected at prenatal diagnosis if a trisomy is detected in just a few cells in chorionic villus or colonies in amniocytes in at least two separate flasks and is confirmed if found in other analyzed fetal/neonatal tissues. Trisomic conditions for some chromosomes are clinically recognized whereas rare trisomy mosaicisms in amniocytes, such as trisomy 2, 3, 5, 9, 12, 14, 15, 16, 22, create some problems in interpretation. There are reports in the literature where only a few cells showing abnormal karyotype with a rare trisomy were seen later to be clinically significant in the newborn infant [Daniel et al., 2004]. The risk of abnormal pregnancy outcome varies depending on the chromosome involved in trisomic mosaic and on the presence of uniparental disomy (UPD). Phenotypic abnormalities in the offspring, IUGR and/or fetal demise or stillbirth, range from moderate to severe [Hsu et al., 1997]. At the reference Regional Center for pregnancies complicated by IUGR (HSGerardo, Monza, Italy), we encountered a 28-year-old primiparous woman with insulin-dependent diabetes mellitus (IDDM type I) at the 26th week of gestation and showing ultrasound diagnosis of intrauterine growth retardation (IUGR) in a morphologically normal fetus. Amniotic fluid analysis showed 41 clones from 9 independent cultures with normal female karyotype (46,XX) and 5 clones from 3 independent cultures with trisomy 5 (47,XX,þ5). Fetal heart monitoring at 30 weeks showed severe variable decelerations. The patient delivered a female infant by Caesarean with Apgar scores of 5/1 and 9/5 and 7.33 cord blood pH. At birth trisomy 5 was also

observed in metaphases from three placental biopsies whereas all analyzed metaphases from cord and peripheral blood (100 and 320, respectively) were normal. Dual color FISH analysis using D5S23 cosmidic probe and the a-satellite centromeric probe for chromosome 16 as control on interphasic placental nuclei confirmed the mosaicism: 64.2% (52/81) of nuclei showed three signals for chromosome 5 and two signals for chromosome 16 and 14.8% (12/81) of nuclei presented normal patterns. The peripheral blood showed disomy in all analyzed cells (174) (parents declined giving permission for biopsy of their baby’s skin). Because of the discrepancy observed between placental and fetal karyotypes, UPD5 was tested and excluded. Physical examination at birth showed: a weight of 740 g (3rd centile), a length of 34 cm (<10th centile), and a head circumference of 26 cm (10th centile). Clinodactyly of the fifth right toe and anterior anus were also noted in the baby. The histological examination of the complete placenta (150 g) showed a decidual vasculopathy. During admission to the neonatal intensive care unit the cerebral sonogram was normal, and a small interatrial shunt had completely disappeared at 11 months. The girl was discharged at 3 months of age, with an increase in length and weight but remaining within the 3rd centile with normal

` *Correspondence to: Dr. Leda Dalpra, University of Milan-Bicocca, Department of Neuroscience & Biomedical Technologies, Via Cadore 48, 20052 Monza (MI), Italy. E-mail: leda.dalpra@unimib.it DOI 10.1002/ajmg.a.31909

American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a


VILLA ET AL. Facial dysmorphism (high-square forehead, hypertelorism, prominent nasal bridge), VSD, diaphragmatic eventration, no cooing at 7 months Died at 9 months (2 months after heart surgery) Skin 46,XY(32)/47,XY,þ5(8)

psychomotor development and normal fundus oculi. Follow-up at 4–6–11–13 months and 3 years of age continued to document growth parameters less than the 3rd centile with normal psychomotor development. Based on data in the literature, excluding marker chromosomes, true mosaicism involves an autosome in 44–47% of cases [Hsu et al., 1996]. Currently a few cases of trisomy 5 mosaicism in prenatal diagnosis have been reported, and thus mosaicism for chromosome 5 frequency is not yet known. IUGR and fetal death have been reported to occur in pregnancies with placental mosaicism for rare trisomies. It remains to be established whether these complications in pregnancies with diploid fetus are due to placental trisomy or are related to fetal UPD. Table I shows the available information on mosaicism confirmation and the long-term follow-up of cases with trisomy 5 mosaicism or non-mosaic fetusplacental discrepancy reported in literature. Trisomy 5 mosaicism in amniotic fluid or in chorionic villus sampling has been reported in eight cases with normal outcome at birth and without evidence of abnormal cell lines in the newborns. Furthermore, three cases without abnormal cell lines in the newborns are reported in EUCROMIC data [Hahnemann and Vejerslev, 1997], but no follow-up data are available. Trisomic cell percentage in the amniocytes did not seem to predict pregnancy outcome: Richkind et al. [1987] reported a case in which 80% of the amniocytes showed trisomic 5 cells, and the pregnancy resulted in a normal liveborn. Moreover in Table I the abnormal cases are reported: Penchaszadeh et al. [1988] described a child with heart murmur and ear pit with low-birth weight and mosaicism for trisomy 5 on amniotic fluid and on cord fibroblasts, and Sciorra et al. [1992] described IUGR in a liveborn dysmorphic male with trisomy 5 mosaicism in skin fibroblasts (20%) and placenta at term (46%). Fryburg et al. [1993] described a case of trisomy 5 detected on cultured CVS: amniotic cells were normal and low-level mosaicism was seen in the fetal testis tissue. In these abnormal cases trisomy 5 was confirmed postnatally in fibroblasts and not found in lymphocytes. It is therefore possible that trisomy 5 mosaicism could be an example of tissuelimited mosaicism with the abnormal cell line surviving in some somatic tissues but not in others. The case described by Reed et al. [1985] exemplifies this point. In fact the trisomy 5, mosaicism observed in a 4-year-old boy with multiple congenital abnormalities and mental retardation, was present in 25% of the analyzed fibroblasts whereas the karyotype on peripheral blood was normal. Our case study presented some minor anomalies such as clinodacty of the small toe of the right foot, anteriorly placed anus, and growth retardation (<3rd centile) with normal psychomotor development, but we cannot exclude the presence of a low-level trisomy

Phenotype (last follow-up)

Normal (6th month)

TABLE I. Summary of Samples With Trisomy 5 Mosaicism or Non-Mosaic Feto-Placental Discrepancy Reported in Literature

Low-birth weight Systolic murmur Preauricular pit Normal (7th month) Liveborn Liveborn 23 (14/60) Casamassima et al. [1989] — 40 (18/45) — Penchaszadeh et al. [1988]

Outcome of pregnancy


% (n) of CVS cells trisomy 5/total

78.9 38 colonies 81.3 16 colonies

% (n) of AF cells trisomy 5/total

Richkind et al. [1987]

Sciorra et al. [1992]

Case identification

25d (6/24) 17 (1/6)


Liveborn IUGR

In utero fetal blood sample 46,XY(100) Peripheral blood 46,XY(103) In utero fetal blood sample 46,XY(100) Cord blood 46,XY(106) Placenta 46,XY(54)/47,XY,þ5(46)

Karyotype (no. of cells) [no. of spots]a

Cord blood 46,XY(100) Foreskin 46,XY(66) Amnion 46,XY(100) Chorion 46,XY(100) Placenta 46,XY(105) Cord 46,XX(92)/47,XX,þ5(8) Bloodc 46,XX


Fryburg et al. [1993] Case II-7 — —

4.5 Culture (3/61) 10.6 Culture (5/47) 100 Culture (50/50)

Liveborn Caesarean for failure to progress 46,XY Abortus Muscle 46,XY(35) Lung 46,XY(35) Skin 46,XY(35) Testis 46,XY(53)/47,XY,þ5(2) 46,XY — Normal growth parameters (23 months)


Normal growth parameters Recurrent otitis media (60 months)

Case II-8

Case III-4

Normal karyotype

Case III-5

4.5 47,þ5 (2/45)f,g

Wang et al. [1993] — — — Liveborn Olygohydramnios and two vessel cord Liveborn IUGR Cord blood 46,XX(100) Peripheral blood 46,XX(320) Cytotrophoblast 47,XX,þ5(3) Mesenchyme 47,XX,þ5(9) FISH on placenta: cytotrophoblast (569)[3], (72)[2]; mesenchyme (111)[3], (30)[2] FISH on blood: nuclei (134)[2], (4)[3]; metaphases (21)[2] No fetal mosaicism 46? No fetal mosaicism 46? 46,XX 46,XY — No fetal mosaicism 46?

EUCROMIC Hahnemann and Vejerslev [1997]

91.1 47,þ20 (41/45) 20 Direct (2/10) 0 Culture (0/50) CPM5 type I Liveborn 46,XX

Recurrent otitis media requiring prophylactic medication or myringotomy tubes Normal development (12.5 months) Normal — — — Normal Normal at delivery and normal development Growth parameter under 3rd percentile (3 years)

Daniel et al. [2004] (10) Culture —

— — 6.7 (2/30) 0 (0/58)

CPM5 type II CPM5 type II — (5) Directc

Our case

11 (15/138)

American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

AF, amniotic fluid; CVS, chorionic villus sample; CPM, confined placental mosaicism; VSD, ventricular septal defect; —, not specified. a Number of spots detected on FISH on nuclei from placenta at term or on blood sample. b Two different amniocenteses. c Total number of analyzed cells not known. d Two different culture vessels. e Number and percentage of cells not known. f Sum of cells from two different culture vessels. g Detection of two different trisomies on CVS.

American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a



5 mosaicism because blood only (and not skin tissue) was available for the analysis. In most cases where trisomy is found on CVS but not on AF, the outcome is normal probably because the trisomy 5 cell line starts as an extraembryonic event or is confined to the placenta and the extra chromosome 5 is lost from the fetus in a rescue process. IUGR and intrauterine demise occurred mainly in pregnancies in which the placental mosaicism was demonstrated at term [Kalousek et al., 1991]. A consequence of trisomic rescue in the fetus could be the UPD, for this reason this event was ruled out in the proposita described here. In literature only a single case of paternal isodisomy for chromosome 5 detected in a child with recessive spinal muscular atrophy (SMA) was reported [Brzustowicz et al., 1994]. No growth and developmental abnormalities, other than those attributable to SMA, were present in the child. This finding therefore suggests that the disorder is due to the paternal SMA gene. Finally, decidual vasculopathy has been reported in association with placental mosaicism, maternal diabetes mellitus, and pregnancy-induced hypertension. In the present case it can be posited that placental mosaicism is the major factor in the IUGR pathogenesis, even if it is not possible to exclude a possible effect of maternal diabetes on the pregnancy. A recent study by Wilkins-Haug et al. [2006] on a sample of 70 newborns with IUGR suggests that there is a significant association of CPM showing idiopathic fetal growth restriction with a frequency of 16%. In conclusion, a diagnosis of trisomy 5 mosaicism provides a challenge in counseling patients because of inadequate information about cytogenetic and clinical follow-up. In order to reach an adequate and more precise genetic counseling in prenatal diagnosis, effort must be made to collect, evaluate, and store cases of mosaicism for rare trisomies.

We would like to thank Dr. D. Colombo, Ph.D, for the excellent technical support.
Brzustowicz LM, Allitto BA, Matseoane D, Michaud L, Chatkupt S, Sugarman E, Penchaszadeh GK, Suslak L, Koenigsberger

MR, Gilliam TC, Handelin BL. 1994. Paternal isodisomy for chromosome 5 in a child with spinal muscular atrophy. Am J Hum Genet 54:482–488. Casamassima AC, Wilmot PL, Mahoney MJ, Scott RV, Shapiro LR. 1989. Trisomy 5 mosaicism in amniotic fluid with normal outcome. Clin Genet 35:282–284. Daniel A, Wu Z, Darmanian A, Malafiej P, Tembe V, Peters G. 2004. Issues arising from the prenatal diagnosis of some rare trisomy mosaics—the importance of cryptic fetal mosaicism. Prenat Diagn 24:524–536. Fryburg JS, Dimaio MS, Yang-Feng TL, Mahoney MJ. 1993. Follow-up of pregnancies complicated by placental mosaicism diagnosed by chorionic villus sampling. Prenat Diagn 13:481–494. Hahnemann JM, Vejerslev LO. 1997. European Collaborative Research On Mosaicism In CVS (EUCROMIC)—Fetal and extrafetal cell lineages in 192 gestations with CVS mosaicism involving single autosomal trisomy. Am J Med Genet 70:179– 187. Hsu LYF, Yu MT, Richkind KE, Van Dyke DL, Crandall BF, Saxe DF, Khodr GS, Mennuti M, Stetten G, Miller WA, Priest JH. 1996. Incidence and significance of chromosome mosaicism involving an autosomal structural abnormality diagnosed through amniocentesis: A collaborative study. Prenat Diagn 16:1–28. Hsu LYF, Yu MT, Neu RL, Van Dyke DL, Benn PA, Bradshaw CL, Shaffer LG, Higgins RR, Khodr GS, Morton CC, Wang H, Brothman AR, Chadwick D, Disteche CM, Jerkins LS, Kalousek DK, Pantzar TJ, Wyatt P. 1997. Rare trisomy mosaicism diagnosed in amniocytes, involving an autosome other than chromosomes 13, 18, 20,and 21: Karyotype/phenotype correlations. Prenat Diagn 17:201–242. Kalousek DK, Howard-Peebles PN, Olson SB, Barrett IJ, Dorfmann A, Black SH, Schulman JD, Wilson RD. 1991. Confirmation of CVS mosaicism in term placentae and high frequency of intrauterine growth retardation association with confined placental mosaicism. Prenat Diagn 11:743– 750. Penchaszadeh VB, Morejon DP, Gervis J, Schwartz M, Mahoney MJ, Babu A. 1988. Prenatally detected trisomy 5 mosaicism in amniotic fluid confirmed in the newborn. Am J Hum Genet 43:A64 (Abstract #256). Reed SD, Hall JG, Riccardi VM, Aylsworth A, Timmons C. 1985. Chromosomal abnormalities associated with congenital contractures (arthrogryposis). Clin Genet 27:353–372. Richkind KE, Apostol RA, Puck SM. 1987. Prenatal detection of trisomy 5 mosaicism with normal outcome. Prenat Diagn 7:143. Sciorra LJ, Hux C, Day-Salvadore D, Lee ML, Mandelbaum DE, Brady-Yasbin S, Fryburg J, Mahoney MJ, Schoenfeld Dimaio M. 1992. Trisomy 5 mosaicism detected prenatally with an affected liveborn. Prenat Diagn 12:477–482. Wang BBT, Rubin CH, Williams J III. 1993. Mosaicism in chorionic villus sampling: An analysis of incidence and chromosomes involved in 2612 consecutive cases. Prenat Diagn 13:179– 190. Wilkins-Haug L, Quade B, Morton CC. 2006. Confined placental mosaicism as a risk factor among newborns with fetal growth restriction. Prenat Diagn 26:428–432.